Analgesic composition



ministered as restoratives and antidotes.

Patented July 6, 1 954 ANALGESIC COMPOSITION Mozes J uda Lewenstein, Kew Gardens, N. Y.

No Drawing.

Application July 28, 1949,

Serial No. 107,389

16 Claims. 1

This invention relates to analgesic and antitussive compositions. to analgesic and antitussive compositions which contain morphine or substances having a morphine-like effect, in mixture with certain other substances which act prophylactically to prevent or reduce the adverse effects of morphine and similar compounds on respiration and/or on the heart.

The main object of my present invention is to provide analgesic and antitussive compositions containing morphine and similar drugs, said compositions causing less depression of respiration and heart rate than encountered in the use of known preparations of morphine and the like.

Another object of my present invention is to provide analgesic and antitussive compositions containing morphine and similar drugs, which can be administered with safety in larger doses .than at present possible, thus producing relief for many of those patients who do not respond at all or do not respond well to the ordinary therapeutic doses of such drugs.

A further object of my present invention is to provide analgesic compositions in which morphine or other drugs having an analgesic and/or cough relieving effect similar to that of morphine are present in mixtures with substances which have a stimulating effect on respiration and/ or on the heart.

Other objects and the advantages of the invention will be apparent from the appended claims and the following specification, which describes some embodiments of the invention.

It is known that in addition to their clinical, useful effects, morphine and drugs having similar action have a depressing effect on respiration anda slowing effect on the heart. These effects represent serious drawbacksin the clinical use of morphine and similar drugs and have often caused dangerous complications in cases of overdoses.

To counteract such dangerous complications, it is a well known practice to administer substances stimulating respiration and/or the heart as antidotes in cases of drug poisoning (barbiturates, opiates, etc). This action is followed when too large a dose of narcotics, etc., has been taken by patients inadvertently; or advertently in suicide attempts. However, it also frequently happens that heart rate or respiration will respond unfavorably to therapeutic doses of narcotics. In such instances, stimulants like pentamethylenetetrazol, nikethamide, etc., are likewise ad- Fur- It has particular relation 7 thermore, in conditions of circulatory or respiratory depression accompanied by pain or cough stimulants as Well as narcotics have been administered, but the stimulant was then given to treat the pre-existing conditions of circulatory or respiratory depression and not as an antidote to a toxic action of the narcotics.

The need for narcotics with less depressing influence on heart rate and respiration has been urgently felt. Many compounds have been synthesized with this purpose in mind and many combinations tried without achieving the desired result.

In studying this problem I tried to find another solution. I did not look for new narcotics Without the undesirable side effects, but I concentrated on the possibility of neutralizing such effects in our existing drugs. I reasoned that once the narcotics are administered, the untoward reactions are bound to occur unless a substance is present in the body, which will not affect the therapeutically useful action of the narcotics, but which may hamper or inhibit the unwished for effects. In addition such a substance should otherwise not exert any action. In looking for such a compound I have now found that the high solubility in water, lipoids,

and other body fluids of a number of heart and respiration stimulants enables me to prevent completely or to a great extent the mentioned adverse effects on the respiration and the heart rate of therapeutic doses of morphine and substances having a similar effect. Such stimulants in therapeutic doses do not affect the normal heart rate or normal respiration, but when narcotics are combined with such stimulants in one dose and administered together, the stimulants are absorbed so fast, that they start their stimulating action, as soon as, or before the adverse symptoms of the narcotics ordinarily would appear. The stimulants provide normal or near normal gaseous interchange in the lungs which interchange is in risk of being reduced and the stimulants are instrumental in preventing or lessening slowing down of the circulation by the narcotics. The favorable effect of the stimulants is enhanced by the fact that their reaction time, i. e. the time between their administration and the start of the stimulant action, is shorter than the reaction time of the narcotics present in the compositions of my invention. The stimulating effect lasts long enough to insure normal or near normal functioning of heart and respiration until the action of the narcotics ebbs off.

In severe cases of pain and cough the relief obtained from the usual maximum doses of narcotics often is quite insuflicient. It has now been found possible to increase the doses of narcotics considerably without endangering the lives of the patients, provided the narcotics are administered in mixtures according to my invention. Thus it is possible to provide much more profound relief than was possible hitherto.

In animal experiments it was found that the lethal dose of such mixtures does not depend upon the amount of narcotics but is determined by the convulsant amount of the stimulant. In clinical use on human beings many thousands of doses of combinations of narcotics and stimulants according to this invention have been given without any serious depression of heart rate or respiration having been reported by any of the numerous hospitals and clinics, where these mixtures have been investigated.

Quite unexpectedly I found that the therapeutic doses of the stimulants usually recommended in narcotic poisoning are not required when the stimulant is given simultaneously with the opiate or compound having a similar action according to the present invention. The quick absorption of the stimulants which I have used insures immediate antagonistic action so that the paralyzing effect of the narcotics cannot take hold of the organism. In addition, the damage caused between the advent of the toxic symptoms and the time required for the antidote to be administered and to take effect is elminated. With simultaneous administration the high solubility of the stimulant provides the presence of the antidote in the circulatory system before the poisoning begins to act thus reducing the required amount of the antidote substantially as compared with the administration of the stimulant once the narcotic has taken effect.

In carrying out the present invention, morphine, morphine-derivatives, and other substances having a morphine-like analgesic and/or antitussive effect, such as codeine, codeine derivatives, l-methyl l-phenyl piperidine l-carboxylic acid ethyl ester and its salts, such as the hydrochloride, 2-dimethylamino-4,4-diphenyl heptanone-5, or its salts, pantopon, methyl-dihydro morphinone or its salts and the like are used. These substances are administered according to the present invention in mixture with substances which stimulate the heart and/ or the respiratory center and have a high solubility in water, lipoids and other body fluids. Examples of such substances are: pentamethylenetetrazol, pyridine beta-carboxylic acid diethylamide, lobeline or its salts, i-cyclohexyl 3-ethyl 1,2,4-triazol, paramethyl-amino-ethanol phenol or its salts.

Example 1 15 mg. of morphine sulfate is homogeneously mixed with 40 mg. pentamethyle-netetrazol and the mixture is administered preferably in dissolved form by injection.

Example 2 100 mg. of ethyl l-methyl-4 phenyl-piperidine- 4-carboxylate hydrochloride is dissolved in 1 cc. of a 25% by weight aqueous solution of pyridinebeta-carboxylic acid diethylamide and the mixture is administered orally or parenterally.

Eatample 3 5 mg. of dihydrocodeinone bitartrate is di"- solved in 1 cc. of an aqueous solution containing 5 mg. lobeline sulfate and preferably given by mouth.

Example 4 4 mg. of dihydromorphinone hydrochloride is mixed with 0.5 mg. of dihydromorphinone homatropine terephthalate and 60 mg. of pentamethylenetetrazol and the mixture injected.

Example 5 4.5 mg. of dihydroxycodeinone hydrochloride is mixed with 0.75 mg. of dihydrohydroxycodeinone homatropine terephthalate and 25 mg. of pentamethylenetetrazol and by preference administered orally. 7

Example 6 10 mg. of codeine phosphate is mixed with mg. of codeine-sodium diethylbarbiturate and 50 mg. of para-methylamine-ethanol-phenol tartrate and taken in a capsule.

The compositions embodying my invention are administered by injections of the dissolved compositions or given by mouth or in the form of a suppository rectally.

It will be understood from the above description that the invention is not limited to the specific substances and process steps described above and may be carried out with various modifications without departing from the scope of the invention as defined in the appended claims. For example, instead of the analgesic substances and the stimulants specifically mentioned in the examples, other substances having a substantially similar eiiect, or mixtures of several such sub stances may be used, and compounds having no adverse effects on the therapeutically useful action of the narcotics and the stimulants used, for example, antispasmodics, may be added to the mixtures embodying the invention.

It is to be understood that the term narcotic substance or narcotic component is used in the present specification and claims to denote morphine, morphine derivatives and other natural or synthetic compounds having a morphinelike therapeutic effect.

What I claim is:

1. A new analgesic composition in which a narcotic component selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine is present in mixture with at least one compound selected from the group of substances stimulating respiration and substances stimulating the heart, said stimulants being easily soluble in water and selected from the group consisting of pentamethylenetetrazol, pyridine beta-carboxylic acid diethylamide, lobeline and its salts, 4-cyclohexyl 3-ethyl l,2/i-triazol, paramethylamine-ethanol phenol and its salts said composition containing the narcotic component and the stimulant in a proportion substantially corresponding to the ratio of 3.75 parts by weight of dihydromorphinone to not more than 60 parts by weight of pentamethylenetetrazol.

2. A new analgesic composition in which a narcotic component selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine is present in mixture with at least one compound selected from the group of substances stimulating respiration and substances stimulating the heart, said stimulants being easily soluble in water and selected from the group consisting of pentamethylenetetrazol, pyridine beta-carboxylic acid diethylamide, lobeline and its salts, i-cyclohexyl 3-ethy1 1,2,4-triazol, paramethylamine-ethanol phenol and its salts, the amount of stimulant per therapeutic dose of the composition being smaller than the therapeutic dose for the adult patient, of the stimulant.

3. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and pentamethylenetetrazol.

4. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and pyridine-beta-carboxylic acid diethylamide.

5. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and a substance selected from the group consisting of lobeline and salts thereof.

6. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and a substance. selected from the group consisting of para-methylamino-ethano1phenol and salts thereof.

7. A composition as claimed in claim 1 comprising in combination a narcotic substance selected from the group consisting of morphine, codeine and narcotic derivatives of morphine and codeine and 4-cyclohexyl 3-ethy1 1,2,4-tria'zol.

8. A composition, as claimed in claim 1, in which a morphine salt is used as the narcotic component.

9. A' composition as claimed in claim 1, in which a dihydrocodeinone salt is used as the narcotic component.

10. A composition as claimed in claim 1, in which a mixture of a simple salt of dihydromorphinone with dihydromorphinone homatropine weight of morphine to about 40 parts 'by weight of pentamethylenetetrazol.

13. A composition as claimed in claim 1 containing as the narcotic ingredient 1-methyl-4 phenyl-piperidine 4-carboxylate hydrochloride and as the stimulant pyridine-beta-carboxylic acid diethylamide, in the proportion of about 87.14 parts by weight of 1-methyl-4 phenylpiperidineA-carboxylate to about 25 parts by weight of pyridine-beta-carboxylic acid diethylamide.

14. A composition as claimed in claim 1, containing as the narcotic compound dihydrocodeinone bitartrate and as the stimulant lobeline sulfate, in the proportion of about 302 parts by weight of dihydrocodeinone to about 4.3 parts by weight of lobeline.

15. A composition as claimed in claim 1,containing as the narcotic compound dihydrohydroxycodeinone hydrochloride, and dihydrohydroxycodeinone homatropine terephthalate and as the stimulant pentamethylenetetrazol, in the proportion of a total amount of about 4.65 parts by Weight of dihydrohydroaycodeinone to about 25 parts by weight of pentamethylenetetrazol.

16. A composition as claimed in claim 1, containing as the narcotic component codeine phosphate and codeine sodium diethylbarbiturate and as the stimulant para-methylamine-ethanol phenol tartrate, in the proportion of a total amount of about 14.40 parts of codeine to about 50.0 parts by weight or" para-methylamine-ethanol phenol.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,027,722 Diehl Jan. 14, 1936 2,369,711 Blythe Feb. 20, 1945 FOREIGN PATENTS Number Country Date 14,961 Great Britain of 1895 OTHER REFERENCES A., Mar. 19, 1949, pages 

1. A NEW ANALGESIC COMPOSITION IN WHICH A NARCOTIC COMPONENT SELECTED FROM THE GROUP CONSISTING OF MORPHINE, CODEINE AND NARCOTIC DERIVATIVES OF MORPHINE AND CODIENE IS PRESENT IN MIXTURE WITH AT LEAST ONE COMPOUND SELECTED FROM THE GROUP OF SUBSTANCES STIMULATING RESPIRATION AND SUBSTANCES STIMULATING THE HEART, SAID STIMULANTS BEING EASILY SOLUBLE IN WATER AND SELECTED FROM THE GROUP CONSISTING OF PENTAMETHYLENETETRAZOL, PYRIDINE BETA-CARBOXYLIC ACID DIETHYLAMIDE, LOBELINE AND ITS SALTS, 4-CYCLOHEXYL 3-ETHYL 1,2,4-TRIAZOL, PARAMETHYLAMINE-ETHANOL PHENOL AND ITS SALTS SAID COMPOSITION CONTAINING THE NARCOTIC COMPONENT AND THE STIMULANT IN A PROPORTION SUBSTANTIALLY CORRESPONDING TO THE RATIO OF 3.75 PARTS BY WEIGHT OF DIHYDROMORPHINONE TO NOT MORE THAN 60 PARTS BY WEIGHT OF PENTAMETHYLENETETRAZOL. 